Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
  • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/06—Anabolic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/12—Ophthalmic agents for cataracts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/26—Androgens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention is directed to method of treating erectile dysfunction and increasing libido in men.
• Standard performance as used herein generally refers to a man's ability to have an orgasm, obtain an erection, or engage in masturbation or intercourse.
• Impotence is a type of deficient sexual performance.
• Impotence or “erectile dysfunction” as used herein is generally refers to the inability of a man to attain an erection with sufficient rigidity for vaginal penetration 25% or more of the times attempted.
• impotence affects about 10% of men in their sixties, 25% of men in their seventies, 40% of men in their eighties, and more than half of those in their nineties. In young couples, the incidence of impotence is about 7%.
• One-third of older men receiving medical treatment also have difficulty with erectile function.
• VIAGRA ® sirolulose citrate USP
• Other drugs useful in the treatment of impotence include, but are not limited to: pentoxifylline (TRENTAL ® ), yohimbine hydrochloride (ACTIBINE ® , YOCON ® ,
• apomorphine is administered orally in a dose of about 2mg to about 3 mg.
• These pharmaceuticals act by a variety of physiological mechanisms. For example, the physiologic mechanism of erection of the penis involves release of nitric oxide ("NO”) in the corpus cavernosum during sexual stimulation.
• NO nitric oxide
• VIAGRA ® has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting phosphodiesterase type 5
• PDE5 which is responsible for degradation of cGMP in the corpus cavernosum.
• UPRIMA ® is a dopamine receptor agonist that acts on the central nervous system. Once absorbed and transported into the brain, UPRIMA ® initiates a chain of reactions that result in increased blood flow to the male genital organs and an erection.
• testosterone plays a beneficial role physiologically, and stimulates both sexual motivation (i.e., libido) and sexual performance.
• Testosterone the major circulating androgen in men, is synthesized from cholesterol. The approximately 500 million Leydig cells in the testes secrete more than 95% of the 6-7 mg of testosterone produced per day. Two hormones produced by the pituitary gland, luteinizing hormone (“LH”) and follicle stimulating hormone (“FSH”), are required for the development and maintenance of testicular function and negatively regulate testosterone production. Circulating testosterone is metabolized to various 17- keto steroids through two different pathways. Testosterone can be metabolized to dihydrotestosterone ("DHT”) by the enzyme 5 ⁇ -reductase or to estradiol (“E 2 ”) by an aromatase enzyme complex.
• DHT dihydrotestosterone
• E 2 estradiol
• Testosterone circulates in the blood 98% bound to protein. In men, approximately 40% of the binding is to the high-affinity sex hormone binding globulin ("SHBG"). The remaining 60% is bound weakly to albumin. Thus, a number of measurements for testosterone are available from clinical laboratories.
• the term “free” testosterone as used herein refers to the fraction of testosterone in the blood that is not bound to protein.
• total testosterone or “testosterone” as used herein means the free testosterone plus protein-bound testosterone.
• bioavailable testosterone refers to the non-SHBG bound testosterone and includes testosterone weakly bound to albumin.
• the present invention relates to a transdermal hydroalcoholic testosterone gel formulation that overcomes the problems associated with other testosterone delivery mechanisms by providing, among other things, a desirable pharmacokinetic hormone profile with little or no skin irritation.
• the gel is used in conjunction with pharmaceuticals aimed at treating erectile dysfunction, such as VIAGRA®, to enhance their effectiveness.
• VIAGRA® erectile dysfunction
• any other steroid in the testosterone synthetic pathway can, if desired, be substituted in whole or in part for testosterone in the methods, kits, combinations, and compositions herein described.
• sildenafil it will be understood that any other pharmaceutical agent for treating erectile dysfunction can, if desired, be substituted in whole or in part for sildenafil in the methods, kits, combinations, and compositions herein described.
• the present invention is directed to methods, kits, combinations, and compositions for improving sexual performance in a subject, for example, a male subject, in need thereof.
• the method comprises delivering to the subject a pharmacologically effective amount of a steroid in the testosterone synthetic pathway in conjunction with a pharmaceutical agent for treating erectile dysfunction.
• the present invention is directed to a method, kit, combination or pharmaceutical composition for percutaneous administration of a steroid in the testosterone synthetic pathway, for example, testosterone, in a hydroalcoholic gel useful for treating erectile dysfunction or libido deficiencies.
• the gel comprises one or more lower alcohols, such as ethanol or isopropanol; a penetration enhancing agent; a thickener; and water.
• the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
• the present invention also includes kits, methods, combinations, and pharmaceutical compositions for reversing, halting or slowing the progression of sexual dysfunction in subject once it becomes clinically evident, or treating the symptoms associated with, or related to the sexual dysfunction.
• the subject may already have a sexual dysfunction at the time of administration, or be at risk of developing sexual dysfunction.
• the pharmaceutical composition of the present invention is administered once, twice, or three times a day, or as many times necessary to achieve the desired therapeutic effect. In another embodiment the composition of the present invention is administered once, twice, or three times a day on alternate days. In another embodiment the composition of the present invention is administered once, twice, or three times a day on a weekly, biweekly, or monthly basis.
• a class of steroids in the testosterone synthetic pathway useful in the methods, kits, combinations, and compositions of the present invention include steroids in the testosterone anabolic or catabolic pathway.
• the active ingredients employed in the present invention may include anabolic steroids such as androisoxazole, androstenedione, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methenolone, methyltrienolone, nandr ⁇ lone, oxymesterone, quinbolone, stenbolone, trenbolone; androgenic steroids such as boldenone, dehydroepiandrosterone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17 alpha-methyltestosterone, 17 alpha-methyl-testosterone 3- cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymetholone, prasterone, stanlolone, stanozolol, dihydrotestosterone, testosterone;
• anabolic steroids such as
• the steroid in the testosterone synthesis pathway is administered in conjunction with another pharmaceutical agent for treating erectile dysfunction, for example, an agent effective at inhibiting the activity of phosphodiesterase, as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents for the treatment of a sexual disorder in a subject ("combination therapy").
• the beneficial effect of the combination includes, 1Q but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents, and also, for example, improving sexual performance such as treating erectile dysfunction and increasing libido in a subject.
• Combination therapy generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
• Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, where each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
• Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single gel having a fixed ratio of each therapeutic agent or in multiple, single capsules, tablets, or gels for each of the therapeutic agents.
• each therapeutic agent can be effected by any appropriate route including, but not limited to, an oral route, a percutaneous route, an intravenous route, an intramuscular route, or by direct absorption through mucous membrane tissues such as by an intranasal route.
• the therapeutic agents can be administered by the same route or by different routes.
• a first therapeutic agent of the combination selected may be administered orally, while the other therapeutic agents of the combination may be administered percutaneously.
• all therapeutic agents may be administered percutaneously, or all therapeutic agents may be administered intravenously, or all therapeutic agents may be administered intramuscularly, or all therapeutic agents can be administered by direct absorption through mucous membrane tissues.
• the sequence in which the therapeutic agents are administered is not narrowly critical.
• Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients, such as, but not limited to, another steroid or other pharmaceutical agents that increase testosterone levels in a subject, and non-drug therapies, such as, but not limited to, surgery.
• other biologically active ingredients such as, but not limited to, another steroid or other pharmaceutical agents that increase testosterone levels in a subject
• non-drug therapies such as, but not limited to, surgery.
• a class of steroids or pharmaceutical agents that increases testosterone levels in a subject useful in the methods, kits, combinations, and compositions of the present invention include compounds that inhibit the synthesis of the sex hormone binding globulin.
• Sex hormone binding globulin is a serum protein, and is believed to bind to testosterone and estradiol, affecting the biological activity of these hormones.
• Specific compounds of interest that inhibit the synthesis the sex hormone binding globulin include but are not limited to methyltestosterone and fluoxymesterone, and all salts, esters, amides, enantiomers, isomers, tautomers, prodrugs and derivatives of these compounds. Combinations of the above these compounds can be used in the methods, kits, combinations, and compositions herein described.
• Methyltestosterone is currently available in various formulations including those available orally, for example, ANDROID® and TESTRED®. Fluoxymesterone is also currently available in various formulations including those available orally, for example, HALOSTES
• the therapeutic compounds which make up the combination therapy may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration.
• the therapeutic compounds that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two step administration.
• a regimen may call for sequential administration of the therapeutic compounds with spaced-apart administration of the separate, active agents.
• the time period between the multiple administration steps may range from, for example, substantially simultaneous, or a few seconds or minutes to several hours to days, depending upon the properties of each therapeutic compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound, as well as depending upon the effect of food ingestion and the age and condition of the subject.
• Circadian variation of the target molecule concentration may also determine the optimal dose interval.
• the steroid of the testosterone pathway is administered within about 24 or 48 hours before the pharmaceutical agent for treating erectile dysfunction.
• the pharmaceutical agent for treating erectile dysfunction is administered within at least one day after the steroid of the testosterone
• the therapeutic compounds of the combined therapy may involve, for example, a regimen calling for administration of one therapeutic compound by oral route or intranasal route and another therapeutic compound by percutaneous route.
• a regimen calling for administration of one therapeutic compound by oral route or intranasal route and another therapeutic compound by percutaneous route may involve, for example, a regimen calling for administration of one therapeutic compound by oral route or intranasal route and another therapeutic compound by percutaneous route.
• the therapeutic compounds of the combined therapy are administered orally, by inhalation spray, intranasal, rectally, topically, buccally (e.g., sublingual), or parenterally (e.g., subcutaneous, intramuscular, intravenous and intradermal injections, or infusion techniques), separately or together, each such therapeutic compound will be contained in a suitable pharmaceutical formulation of pharmaceutically-acceptable excipients, diluents or other formulations components. Examples of suitable pharmaceutically-acceptable formulations containing the therapeutic compounds are provided herein.
• the present invention is also useful for veterinary treatment of mammals, reptiles, birds, exotic animals and farm animals, including mammals, rodents, and the like.
• the mammal includes a primate, for example, a human, a monkey, or a lemur, a horse, a dog, a pig, or a cat.
• the rodent includes a rat, a mouse, a squirrel or a guinea pig.
• the methods, kits, combinations, and compositions of the present invention provide enhanced treatment options for treating sexual dysfunction in a subject, for example, a man, as compared to those currently available.
• compositions of the present invention are the isomeric forms and tautomers of the described compounds and the pharmaceutically-acceptable salts thereof.
• Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galacta
• the steroid of the testosterone pathway and the pharmaceutical agent for treating erectile dysfunction comes in the form of a kit or package containing one or more of the therapeutic compounds of the present invention.
• These therapeutic compounds of the present invention can be packaged in the form of a kit or package in which hourly, daily, weekly, or monthly (or other periodic) dosages are arranged for proper sequential or simultaneous administration.
• the present invention further provides a kit or package containing a plurality of dosage units, adapted for successive daily administration, each dosage unit comprising at least one of the therapeutic compounds of the present invention.
• This drug delivery system can be used to facilitate administering any of the various embodiments of the therapeutic compounds of the present invention.
• the system contains a plurality of dosages to be to be administered daily or weekly.
• the kit or package can also contain the agents utilized in combination therapy to facilitate proper administration of the dosage forms.
• the kits Or packages also contain a set of instructions for the subject.
• the present invention employs a packet having a polyethylene liner compatible with the components of a testosterone gel, as described below.
• the packet may hold a unit dose or multiple dose.
• the methods, kits, combinations, and compositions employ a composition that is dispensed from a rigid multi-dose container (for example, with a hand pump) having a larger foil packet, for example, of the composition inside the container.
• a rigid multi-dose container for example, with a hand pump
• Such larger packets can also comprise a polyethylene liner as above.
• prodrug refers to a drug or compound in which the pharmacological action (active curative agent) results from conversion by metabolic processes within the body.
• Prodrugs are generally considered drug precursors that, following administration to a subject and subsequent absorption, are converted to an active or a more active species via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body.
• Prodrugs generally have a chemical group present on the prodrug which renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved from the prodrug the more active drug is generated.
• Prodrugs may be designed as reversible drug derivatives and utilized as modifiers to enhance drug transport to site-specific tissues.
• prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent.
• Fedorak, et al., Am. J. Physiol, 269:G210-218 (1995) describe dexamethasone- beta r D- glucuronide.
• McLoed, et al., Gastroenterol., 106:405-413 (1994) describe dexamethasone-succinate-dextrans.
• Hochhaus, et al., Biomed. Chrom., 6:283-286 (1992) describe dexamethasone-21 -sulphobenzoate sodium and dexamethasone-21 -isonicotinate.
• prodrugs that can be used in the combinations and methods of the present invention include parecoxib (propanamide, N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]-), and MAG- camptothecin.
• derivative refers to a compound that is produced from another compound of similar structure by the replacement of substitution of one atom, molecule or group by another.
• a hydrogen atom of a compound may be substituted by alkyl, acyl, amino, etc., to produce a derivative of that compound.
• penetration enhancing agent refers to an agent that accelerates the delivery of the drug through the skin.
• These agents also are referred to as accelerants, adjuvants, and absorption promoters, and are collectively referred to herein as “enhancers.”
• This class of agents includes those with diverse mechanisms of action including those which have the function of improving the solubility and diffusibility of the drug, and those which improve percutaneous absorption by changing the ability of the stratum corneum to retain moisture, softening the skin, improving the skin's permeability, acting as penetration assistants or hair-follicle openers or changing the state of the skin such as the boundary layer.
• the penetration enhancing agent of the present invention is a functional derivative of a fatty acid, which includes isosteric modifications of fatty acids or non-acidic derivatives of the carboxylic functional group of a fatty acid or isosteric modifications thereof.
• the functional derivative of a fatty acid is an unsaturated alkanoic acid in which the — COOH group is substituted with a functional derivative thereof, such as alcohols, polyols, amides and substituted derivatives thereof.
• fatty acid means a fatty acid that has four (4) to twenty-four (24) carbon atoms.
• Non-limiting examples of penetration enhancing agents include C8-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6- C22 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl ether
• the thickening agents, or gelling agents, used herein may include anionic polymers such as polyacrylic acid (CARBOPOL® by B.F. Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), carboxypolymethylene, carboxymethylcellulose and the like, including derivatives of Carbopol® polymers, such as Carbopol® Ultrez 1 , Carbopol® 940, Carbopol® 941 , Carbopol® 954, Carbopol® 980, Carbopol® 981 ,
• anionic polymers such as polyacrylic acid (CARBOPOL® by B.F. Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), carboxypolymethylene, carboxymethylcellulose and the like, including derivatives of Carbopol® polymers, such as Carbopol® Ultrez 1 , Carbopol® 940, Carbopol® 941 , Carbopol® 954, Carbopol® 980, Carbopol® 981
• the term "lower alcohol,” alone or in combination, means a straight-chain or branched-chain alcohol moiety containing one to about six carbon atoms. In one embodiment, the lower alcohol contains one to about 4 carbon atoms, and in another embodiment the lower alcohol contains two to about 3 carbon atoms. Examples of such alcohol moieties include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.
• lower alkyl means a straight- chain or branched-chain alkyl radical containing one to about six carbon atoms. In one embodiment, the lower alkyl contains one to about four carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert- butyl.
• the composition is used in a "pharmacologically effective amount.” This means that the concentration of the drug administered is such that in the composition it results in a therapeutic level of drug delivered over the term that the drug is to be used. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the flux rate of the drug from the composition, for example, testosterone, from the gel, surface area of application site, etc. For testosterone, for example, the amount of testosterone necessary can be experimentally determined based on the flux rate of testosterone through the gel, and through the skin when used with and without enhancers.
• certain formulations of the present invention deliver about 0.01 g to about 100 g testosterone, or the equivalent thereof, to a subject per dosage unit. In another embodiment of the present invention, the formulations deliver from about 0.1 g to about 10 g testosterone, or the equivalent thereof, to a subject per dosage unit. In yet another embodiment of the present invention, the formulations of the present invention deliver from about 0.17 g to about 5 g testosterone, or the equivalent thereof, to a subject per dosage unit. In another embodiment of the present invention, the formulations of the present invention deliver about 1 g testosterone, or the equivalent thereof, to a subject per dosage unit. In still another embodiment of the present invention, the formulations of the present invention deliver about 0.25 g testosterone, or the equivalent thereof, to a subject per dosage unit.
• a testosterone gel, ointment, cream or patch is formulated as a single dosage unit for once a day administration contains about 0.17 g, or about 0.25 g, or about 0.5 g testosterone, or about 1.0 g testosterone, while a gel, ointment, cream or patch formulated as a single dosage unit for once a week administration contains about 1.19 g, or about 1.75 g, or about 3.50 g, or about 7.0 g testosterone, respectfully.
• the formulation is a gel, an ointment, a cream or a patch and is comprised of testosterone; a penetration enhancing agent, such as isopropyl myristate; a thickening agent, such as Carbopol; a lower alcohol, such as ethanol or isopropanol; and water.
• a penetration enhancing agent such as isopropyl myristate
• a thickening agent such as Carbopol
• a lower alcohol such as ethanol or isopropanol
• water water.
• the formulation is a gel, an ointment, a cream or a patch and is comprised of the following substances in approximate percentages:
• the gel, ointment, cream, or patch may contain about 0.01 g to about 70 g of testosterone, about 0-01 g to about 50 g penetration enhancing agent, about 0.1 g to about 50 g thickening agent, and about 30 g to about 98 g lower alcohol.
• the gel, ointment, cream, or patch may contain about 0.1 g to 10 g of testosterone, about 0.1 g to about 5 g of penetration enhancing agent, about 0.1 g to about 5 g of thickening agent, an about 45 g to about 90 g lower alcohol.
• the composition is a gel, ointment, cream, or patch that further comprises a hydroxide releasing agent, such as sodium hydroxide (for example, 0.1 N NaOH), in an amount of about 0.1% to about 10% w/w of the composition.
• a hydroxide releasing agent such as sodium hydroxide (for example, 0.1 N NaOH)
• the pharmaceutical composition includes about 0-5% to about 10% testosterone; about 30% to about 98% alcohol, for example, ethanol or isopropanol; about 0.1% to about 5% isopropyl myristate; about 1% to about 5% sodium hydroxide; and about 0.1% to about 5% of a gelling agent.
• the percentages of components are weight to weight of the composition.
• the pharmaceutical composition includes testosterone in a hydroalcoholic gel. The testosterone may be present in a concentration of about 0-5%,
• the enhancer in this embodiment includes isopropyl myristate, which may be present in a concentration of about 0.5%, 1%, 2%, 3%, 4%, or 5% weight to weight of the composition.
• the pharmaceutical composition also includes a C1-C4 alcohol present in a concentration of about 72.5% weight tp weight of the composition.
• the pharmaceutical composition includes polyacrylic acid and/or carboxymethylcellulose as the gelling agent.
• the gelling agent is polyacrylic acid present in a concentration of about 1% weight to weight of the composition.
• the gel is comprised of the following substances in approximate amounts:
• composition may contain about 0-1 to about 10.0 g of testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl myristate, and about 30.0 to about 98.0 g ethanol.
• the composition comprises testosterone in an amount greater than 0.01%, a penetration enhancing agent in an amount greater than about .0.1%, a thickening agent in an amount greater than about 0.1 %, and a lower alcohol in an amount greater than about 30% w/w of the composition.
• the gel, ointment, cream, or patch is rubbed or placed onto an area of skin of the subject and allowed to dry.
• the gel, ointment, or cream is rubbed onto an area of skin, for example, on the upper outer thigh and/or hip once daily.
• the subject washes his or her hands.
• Application of the gel results in an increased testosterone level having a desirable pharmacokinetic profile effective to treat or prevent sexual dysfunction, or the symptoms associated with, or related to sexual dysfunction in the subject.
• the composition is thus useful for treating a number of sexual dysfunctions, disorders, conditions or diseases in both men and women.
• a method for treating, preventing sexual dysfunction in a subject in need thereof, that is, a subject indicated for having, or at risk of developing sexual dysfunction comprises administering a pharmacologically effective amount of a composition to an area of skin of the subject for delivery of a steroid in the testosterone synthetic pathway to blood serum of the subject.
• the composition comprises:
• the composition is capable of releasing the steroid after applying the composition to the skin at a rate and duration that delivers in one embodiment of the present invention at least about 10 ⁇ g per day of the steroid to the blood serum of the subject.
• the steroid in the testosterone synthetic pathway is testosterone.
• the composition is capable of releasing the testosterone after applying the composition to the skin of a subject at a rate and duration that achieves a circulating serum concentration of testosterone greater than about 400 ng per dl serum during a time period beginning about 2 hours after administration and ending about 24 hours after administration.
• the composition is capable of releasing the testosterone after applying the composition to the skin of a subject at a rate and duration that achieves a circulating serum concentration of the testosterone between about 400 ng testosterone per dl serum to about 1050 ng testosterone per dl serum.
• kits, combinations, and compositions of the present invention for each about 0.1 gram per day application of the composition of the present invention to the skin of a subject, an increase of at least about 5 ng/dl in serum testosterone concentration results in the subject.
• the composition of the present invention is provided to a subject for daily administration in about a 0.1 g to about a 10 g dose.
• the subject in need of treatment has a serum testosterone level before the first application (pretreatment) of the composition of the present invention of less than about 300 ng/dl.
• the serum testosterone concentration in a subject is at least about 490 ng/dl to about 860 ng/dl.
• kits, combinations, and compositions of the present invention where after at least about 30 days of daily administration of the composition of the present invention the total serum androgen concentration in a subject is greater than about 372 ng/dl.
• composition of the present invention is administered once, twice, or three times daily to a subject for at least about 7 days.
• the present invention also provides a method of treating, preventing or reducing the risk of developing sexual dysfunction in a subject in need thereof, that is, a subject indicated for having, or at risk of developing sexual dysfunction, by administering to the subject: (a) an amount of a composition comprising:
• composition is administered tp an area of skin of the subject for delivery of the steroid in the testosterone synthetic pathway to the blood serum of the subject, and is capable of releasing the steroid after applying the composition to the skin at a rate and duration that delivers at least about 10 ⁇ g per day of the steroid to the blood serum of the subject.
• the amount pf the composition and the amount of the therapeutic agent together make a pharmacologically effective amount.
• kits, combinations, and compositions of the present invention the composition and the therapeutic agent are provided as separate components to a kit.
• the composition and the therapeutic agent are administered substantially simultaneously, or sequentially.
• the therapeutic agent is administered orally, percutaneously, intravenously, intramuscularly, or by direct absorption through mucous membrane tissue.
• the present invention also provides a pharmaceutical composition, comprising:
• a therapeutic agent for treating erectile dysfunction (v) a therapeutic agent for treating erectile dysfunction.
• the composition is administered to an area of skin of the subject for delivery of the testosterone and the therapeutic agent to the blood serum of the subject, and is capable pf releasing the steroid after applying the composition to the skin at a rate and duration that delivers at least about 10 ⁇ g per day of the steroid to the blood serum of the subject.
• the amount of the testosterone and the amount of the therapeutic agent together make an ampunt sufficient tp treat erectile dysfunctipn in a subject.
• Achieving target delivery rates demonstrated by testosterone gel can be estimated from the pharmacokinetics in testosterone gel in men.
• the mean serum concentration (Cavg) values in men after applying of varying amounts of gel to the upper body is given in the Table below.
• Table 5 Mean Average Serum Testosterone Concentrations and Daily Delivery Rate after Administration of Testosterone Gel 1% in Men
• a testosterone gel dose of 0.5 grams delivers approximately 300 ⁇ g of testosterone per day.
• Toxicity and therapeutic efficacy of the active ingredients can be determined by standard pharmaceutical procedures, e.g., for determining LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
• Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects
• AndroGel® may also be used in combination with pharmaceuticals useful for treating erectile dysfunction.
• Such pharmaceuticals include any agent that is effective to inhibit the activity of a phosphodiesterase.
• Suitable phosphodiesterase inhibitors include, but are not limited to, inhibitors of the type III phosphodiesterase (cAMP-specific-cGMP inhibitable form), the type IV phosphodiesterase (high affinity-high specificity cAMP form) and the type V phosphodiesterase (the cGMP specific form). Additional inhibitors that may be used in conjunction with the present invention are cGMP-specific phosphodiesterase inhibitors other than type V inhibitors.
• type III phospodiesterase inhibitors that may be administered include, but are not limited to, bypyridines such as milrinone and amirinone, imidazolones such as piroximone and enoximone, dihydropyridazinones such as imazodan, 5-methyl-imazodan, indolidan and ICI1118233, quinolinone compounds such as cilostamide, cilostazol and vesnarinone, and other molecules such as bemoradan, anergrelide, siguazodan, trequinsin, pimobendan, SKF-94120, SKF-95654, lixazinone and isomazole.
• bypyridines such as milrinone and amirinone
• imidazolones such as piroximone and enoximone
• dihydropyridazinones such as imazodan, 5-methyl-imazodan, indolidan and ICI11
• type IV phosphodiesterase inhibitors suitable herein include, but are not limited to, rolipram and rolipram derivatives such as RO20-1724, nitraquazone and nitraquazone derivatives such as CP-77059 and RS-25344-00, xanthine derivatives such as denbufylline and ICI63197, and other compounds such as EMD54622, LAS-31025 and etazolate.
• type V phosphodiesterase inhibitors include, but are not limited to, zaprinast, MY5445, dipyridamole, vardenafil and sildenafil.
• Other type V phosphodiesterase inhibitors are disclosed in PCT Publication Nos. WO 94/28902 and
• an inhibitor of phosphodiesterase type 5 such as VIAGRA ® (sildenafil citrate USP) is administered in an amount of about 25 mg to 200 mg.
• sildenafil citrate is administered orally in a dose of about 25 mg, 50 mg, or 100 mg.
• sildenafil citrate is administered intranasally in an amount of about 10 mg, 20 mg, or 40 mg.
• U.S. Patent No. 6,200,591 discloses the intranasal administration of sildenafil.
• the compounds described in PCT Publication No. WO 94/28902 are pyrazolopyrimidinones.
• the inhibitor compounds include 5-(2-ethoxy-5- morpholinoacetylphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7H-p yrazolo[4,3-d]pyrimidin- 7-one, 5-(5-morpholinoacetyl-2-n-propoxyphenyl)- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7 -H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-l-piperazinyIsulfonyl)- phenyl] 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H-pyra
• the phosphodiesterase inhibitors described in PCT Publication No. WO 96/16644 include griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone derivatives, fused and condensed pyrimidines, pyrimidopyrimidine derivatives, purine compounds, quinazoline compounds, phenylpyrimidinone derivative, imidazoquinoxalinone derivatives or aza analogues thereof, phenylpyridone derivatives, and others.
• 96/16644 include l,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2- propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)- 1 ,2-dihydro-2-oxypyridine-3- carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one, 7-methylthio-.4-oxo- 2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidi ne, 6-hydroxy-2-(2- propoxyphenyl)pyrimidine-4-carboxamide, 1 -ethyl-3-methylirnidazo[ 1 ,5a]quinoxalin- 4(5H)-one, 4-phenylmethylamino-6-chloro-2-(l-imidazoloyl)quinazoline, 5-ethyl-8-[
• Still other type V phosphodiesterase inhibitors useful in conjunction with the present invention include: IC-351 (ICOS); 4-bromo-5-(pyridyImethylamino)-6-[3-(4- chlorophenyl)propoxy]-3(2H)pyridazi none; l-[4-[(l,3-benzodioxol-5-ylmethyl)amiono]- 6-chloro-2-quinazolinyl]-4-piper idine-carboxylic acid, monosodium salt; (+)-cis- 5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenymmethyl-5-meth yl-cyclopent-
• the pharmaceutical or therapeutic agents for treating erectile dysfunction may be administered, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method.
• Salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley- Interscience, 1992).
• acid addition salts are prepared from the free base using conventional methodology, and involves reaction with a suitable acid.
• the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto.
• the resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent.
• Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• organic acids e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
• An acid addition salt may be reconverted to the free base by treatment with a suitable base.
• Particularly preferred acid addition salts of the active agents herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids.
• preparation of basic salts of acid moieties which may be present on a phosphodiesterase inhibitor molecule are prepared in a similar manner using a pharmaceutically acceptable base such. as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.
• Particularly preferred basic salts herem are alkali metal salts, e.g., the sodium salt, and copper salts.
• esters involves functionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure of the drug.
• the esters are typically acyl- substituted derivatives of free alcohol grpups, i.e., mpieties which are derived frpm carbpxylic acids pf the fprmula RCOOH where R is alkyl, and preferably is lpwer alkyl.
• Esters can be recpnverted tp the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
• Amides and prodrugs may also be prepared using techniques known to those skilled in the art or described in the pertinent literature.
• amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
• Prodrugs are typically prepared by covalent attachment of a moiety, which results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
• TRENTAL ® pentoxifylline
• ACTIBINE ® yohimbine hydrocholoride
• a testosterone containing gel such as AndroGel® is administered to increase and enhance the therapeutic effectiveness of such drugs, in either hypogonadal or eugonadal men having erectile dysfunction.
• the testosterone gel used in accordance with the present invention plays a beneficial rple physiplogically, and stimulates bpth sexual mptivatipn (i.e., libido) and sexual performance.
• Testosterone controls the expression of the nitric oxide synthase gene. See
• AndroGel® is applied tp the bpdy in accprdance with the protocol summarized in Example 1.
• the pharmaceutical(s) for erectile dysfunction is taken in accordance with the prescription requirements.
• VIAGRA® is generally taken 20-40 minutes before sexual intercourse in 50 mg doses.
• This combination of therapy is particularly useful in hypogpnadal men who need increased testosterone levels in order to optimize the effects of VIAGRA® and the sexual experience as a whole. In essence, a therapeutic effect is obtained.
• AndroGel® is preferably applied to the body for a sufficient number of days so that the steady-state levels of testosterone are achieved.
• Example l ⁇ Testosterone gel plus Sildenafil Improves sexual Performance in Sildenafil Non-Responders
• One embodiment of the present invention involves the transdermal application of a testosterone gel co-administered with an oral dose of sildenafil as a method of producing an erectile response in hypogonadal men who do not respond to treatment with sildenafil alone fpr erectile dysfunctipn.
• hypogonadal men who did not respond tp sildenafil alone in the treatment of erectile dysfunction were recruited and studied in several centers across the United States.
• the study was double-blind for a testosterone gel 1 % (Androgel®) and a placebo gel.
• the mean age of the patients was 58.5 years.
• the IIEF is a brief, reliable, self-administered questionnaire of erectile function utilized in cross cultural settings for detecting treatment-related changes in patients.
• the IIEF consists of 15 questions directed to individual sexual performance. Each question includes
• Androgel® (delivering 50 mg/day of testosterone to the skin of which about 1Q% or 5 mg is absorbed) plus 100 mg of sildenafil (1 hour before intercourse) or 5.0 g/day placebo gel plus 100 mg of sildenafil (1 hour before intercourse).
• the patients were treated for 12 weeks.
• An interim analysis on 67 subjects at Week 4 showed that Androgel® significantly improved response to sildenafil on EF, OF, and OS domains, and IIEF Total
• the primary outcome measures included the mean change from baseline (BL) in the Erectile Function domain of the IIEF. Secondary outcome measures included the mean change from baseline in each of the remaining four domains and total score of the IIEF.
• Safety assessments included a physical exam, urologic exam, PSA, vital signs, laboratory tests and adverse events.
• testosterone replacement therapy with testosterone-gel improves erectile response to sildenafil and may be utilized in the treatment of erectile dysfunction in men with low to low-normal testosterone who failed prior treatment with sildenafil alone.
• AndroGel® 1% testosterone gel formulation was employed in this study, the present invention is not limited to only this one embodiment. Other embodiments may use higher or lower amounts of androgen, penetration enhancer(s) and excipients to achieve the present invention.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Endocrinology (AREA)
• Diabetes (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Reproductive Health (AREA)
• Neurology (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Physical Education & Sports Medicine (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Heart & Thoracic Surgery (AREA)
• Gynecology & Obstetrics (AREA)
• Cardiology (AREA)
• Psychiatry (AREA)
• Rheumatology (AREA)
• Ophthalmology & Optometry (AREA)
• Virology (AREA)
• Dermatology (AREA)
• Inorganic Chemistry (AREA)
• AIDS & HIV (AREA)
• Child & Adolescent Psychology (AREA)
• Molecular Biology (AREA)
• Tropical Medicine & Parasitology (AREA)

Priority Applications (6)

Applications Claiming Priority (2)

Publications (2)

Family

ID=32174519

Family Applications (1)

Country Status (7)

Cited By (13)

Families Citing this family (40)

Citations (4)

Family Cites Families (34)

• 2002
  • 2002-10-18 US US10/273,484 patent/US20030139384A1/en not_active Abandoned
• 2003
  • 2003-10-16 EP EP03809561A patent/EP1551416A4/en not_active Withdrawn
  • 2003-10-16 CA CA002502607A patent/CA2502607A1/en not_active Abandoned
  • 2003-10-16 JP JP2004546863A patent/JP2006505587A/ja active Pending
  • 2003-10-16 AU AU2003277388A patent/AU2003277388A1/en not_active Abandoned
  • 2003-10-16 US US10/531,526 patent/US20060211664A1/en not_active Abandoned
  • 2003-10-16 WO PCT/US2003/032597 patent/WO2004037173A2/en active Application Filing
  • 2003-10-16 MX MXPA05004093A patent/MXPA05004093A/es active IP Right Grant
• 2004
  • 2004-06-14 US US10/867,435 patent/US20050049233A1/en not_active Abandoned

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events